Oxidative stress in brain injury: Cerebroprotection by endogenous antioxidants

Abstract

Cocaethylene is an active cocaine metabolite formed by hepatic carboxylesterases in the presence of alcohol. The effects of cocaethylene on the hypothalamic-pituitary-adrenal (HPA) axis were investigated in vivo using adrenocorticotropic hormone (ACTH) and corticosterone secretion as indices of peripheral stimulation. To ascertain the central effects of cocaethylene on discrete neurons of the paraventricular nucleus (PVN) of the hypothalamus, a specific cRNA probe was used to follow changes in the transcriptional activation of nerve growth factor I-B (NGFI-B), a member of the family of immediate-early genes. Intravenous (i.v.) injection of cocaethylene (16 μmol/kg) to rats produced a marked but transient increase in plasma levels of ACTH and corticosterone within 10 min of drug exposure. Secretion of these hormones was accompanied by elevated levels of NGFI-B mRNA detected 30 min after i.v. or intraperitoneal (i.p., 60 μmol/kg) cocaethylene administration. The transcriptional stimulation of this immediate-early gene within parvocellular secretory neurons was relatively brief in duration, returning to basal levels by 180 min after drug exposure. As expected, both routes of cocaethylene administration produced an increase in locomotor activity compared to saline-vehicle rats, with no differences between i.v. or i.p. routes with respect to duration of behavioral activation. Taken together, these findings indicate that cocaethylene has neuroendocrine properties on its own, targeting a critical region of the brain that regulates stressful events in the body. This, combined with other neurochemical properties, points to the possibility of cocaethylene augmenting the effects of a drug-dependent state.